PROJECT SUMMARY Heart failure is a complex and heterogeneous syndrome that imposes a substantial burden on public health. Despite decades of investment in basic research in cardiomyocyte biology, pharmacotherapy exclusively targets the neurohormonal response to heart failure and does not directly target myocyte dysfunction. The substantial investment in understanding myocyte biology thus remains untranslated to patient benefit. Approaches that have appeared promising in animal models have frequently proven ineffective in human subjects, casting doubt on the relevance of such models alone to identify the most compelling targets. Genome science in very large population samples has now matured to the point where targets of in vivo relevance in humans can be identified directly through genetic association alone. Human genomics thus provides a roadmap for target selection and a focus for experiments in model systems and drug development. Using a combination of population genomic, transcriptomic, and epigenomic approaches, we have uncovered compelling evidence supporting MTSS1 as a therapeutic target for human myocardial disease. In our preliminary studies, we have found that genetic variants within a cardiac-specific enhancer reduce expression of MTSS1 specifically in the left ventricle and associate with multiple cardioprotective phenotypes in human populations, including reduced left ventricular (LV) mass, reduced LV diameter, increased fractional shortening, and reduced risk of dilated cardiomyopathy. Further, we have found that Mtss1 knockout mice have a baseline cardiac phenotype that parallels findings in humans (reduced LV mass, LV dimension, and increased ejection fraction). These findings motivate our central hypothesis that reduction of MTSS1 will be cardioprotective for myocardial diseases. The overall goals of this proposal are to (1) refine the patient subgroup(s) that might benefit the most from MTSS1 reduction, (2) establish causality of the association between reduced MTSS1 and cardioprotection, and (3) modulate cardiac MTSS1 expression in vivo to assess therapeutic effects and protein biology.